Interpreting Breast International Group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer

Meredith M Regan, Karen N Price, Anita Giobbie-Hurder, Beat Thürlimann, Richard D Gelber, International Breast Cancer Study Group and BIG 1-98 Collaborative Group

Abstract

The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one followed by 3 years of the other for postmenopausal women with endocrine-responsive early invasive breast cancer. From 1998 to 2003, BIG -98 enrolled 8,010 women. The enhanced design f the trial enabled two complementary analyses of efficacy and safety. Collection of tumor specimens further enabled treatment comparisons based on tumor biology. Reports of BIG 1-98 should be interpreted in relation to each individual patient as she weighs the costs and benefits of available treatments. Clinicaltrials.gov ID: NCT00004205.

Figures

Figure 1
Figure 1
Design of the Breast International Group 1-98 trial. The design allows both head-to-head comparison of letrozole monotherapy versus tamoxifen monotherapy (4,922 patients) and assessment of the role of sequential endocrine treatments (6,182 patients). Neoadj CT, neoadjuvant chemotherapy.
Figure 2
Figure 2
Inverse probability of censoring weighted Cox model results of the comparison of the monotherapy arms of Breast International Group 1-98 at median follow-up of 74 months. Comparisons for (a) primary and secondary endpoints and (b) subgroups with overall survival (OS) endpoint are shown. The size of the boxes is inversely proportional to the standard errors of the hazard ratio. The solid vertical line is placed at 0.82, which is the hazard ratio estimate for the overall analysis of the OS endpoint. CI, confidence interval; ER, estrogen receptor; L, letrozole; Nx, regional lymph nodes not examined; PgR, progesterone receptor; T, tamoxifen. *Other includes ER+/PgR unknown, ER unknown/PgR+, ER-/PgR- (ineligible), ER-/PgR unknown, and ER unknown/PgR unknown. Reprinted with permission from the Journal of Clinical Oncology [13]. Copyright 2011, American Society of Clinical Oncology.
Figure 3
Figure 3
Cox model results for the sequential treatments (four-arm option) compared with letrozole monotherapy at median follow-up of 71 months. (a) Tamoxifen followed by letrozole versus letrozole monotherapy. (b) Letrozole followed by tamoxifen versus letrozole monotherapy. Both analyses were stratified for chemotherapy use. The size of the boxes is inversely proportional to the standard error of the hazard ratio. As specified in the protocol to account for multiple comparisons, 99% confidence intervals are shown. Results are shown for the diseasefree survival, overall survival, and time to distant recurrence endpoints. Interaction tests between treatment and nodal status are not statistically significant. CI, confidence interval; Let, letrozole; Nx, regional lymph nodes not examined; Tam, tamoxifen. Reprinted with permission from The New England Journal of Medicine [12]. Copyright 2009, Massachusetts Medical Society.
Figure 4
Figure 4
Disease-free survival according to central and local classification of hormone receptor status. Kaplan-Meier estimates at a median follow-up of 4 years for 3,610 patients on the monotherapy arms of Breast International Group 1-98 with adequate tumor material for central assessment of hormone receptors. The two receptors are combined to define an overall assessment of hormone receptor status. Positive refers to estrogen receptor-positive or progesterone receptor-positive or both, and negative indicates that both are negative. DFS, disease-free survival; HR, hormone receptor; SE, standard error. Reprinted with permission from the Journal of Clinical Oncology [19]. Copyright 2007, American Society of Clinical Oncology.
Figure 5
Figure 5
STEPP analysis of 5-year disease-free survival (DFS) according to level of centrally assessed tumor markers. (a) Estrogen receptor (ER) status, (b) progesterone receptor (PgR) status, (c) Ki-67 labeling index status, and (d) HER2 status for 5,177 assessable patients enrolled in the four-arm option at a median follow up of 71 months. Rug plots along the x-axis display the distribution of individual values. Let, letrozole; STEPP, Subpopulation Treatment Effect Pattern Plot; Tam, tamoxifen. Reprinted with permission from Annals of Oncology [23]. Copyright 2011, Oxford University Press.
Figure 6
Figure 6
STEPP analysis of 5-year disease-free survival according to level of composite measure of prognostic risk. Plots include the 5,177 assessable patients enrolled in the four-arm option at a median follow-up of 71 months. (a) Treatment groups combined and (b) according to randomized treatment group. Rug plots along the x-axis display the distribution of individual values. DFS, disease-free survival; Let, letrozole; STEPP, Subpopulation Treatment Effect Pattern Plot; Tam, tamoxifen. Reprinted with permission from Annals of Oncology [23]. Copyright 2011, Oxford University Press.
Figure 7
Figure 7
Forest plot showing the relative risk of an adverse event. Grades 1 to 5 (a) and grades 3 to 5 (b) among the 4,895 patients who were assigned tamoxifen or letrozole monotherapy and who received some trial treatment. All patients had completed treatment (median follow-up of 76 months). AE, adverse event; CI, confidence interval; CVA/TIA, cerebral vascular accident/transient ischemic attack; MedDRA, Medical Dictionary for Regulatory Activities.
Figure 8
Figure 8
Kaplan-Meier cumulative incidence estimates of time to first occurrence of four targeted adverse events. Cumulative incidence estimates of (a) cardiac events (any grade), (b) thromboembolic events (any grade), (c) osteoporosis (grade 3) or bone fractures (any grade), and (d) hot flushes or night sweats (any grade) are shown. Letrozole is compared with tamoxifen among the 4,895 patients who were assigned tamoxifen or letrozole monotherapy and who received some trial treatment. All patients had completed treatment (median follow-up of 76 months). AE, adverse event. Reprinted with permission from the Journal of Clinical Oncology [13]. Copyright 2011, American Society of Clinical Oncology.

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